We have demonstrated that the physiological state of the lumbosacral spinal circuitry of spinal rats and cats can be modulated with spinal cord epidural stimulation (EDS) and/or administration of pharmacological agents to generate weight-bearing standing and stepping over a range of speeds, loads, and directions. We have translated some of these results to humans by implanting 3 motor complete spinal cord injured (SCI) subjects about three years post-injury with an epidural electrode array over the lumbosacral spinal cord. In less than one month post-electrode implant, the subjects could stand independently, and after up to 7 months of daily EDS and motor training, voluntary control of both legs was evident in the presence of EDS, whereas complete paralysis remained in absence of EDS. We propose to employ a similar stimulation strategy for the recovery of upper limb function. We will include extensive testing of spinal rats to guide our strategy to test for upper extremity improvement in human SCI subjects. We will use off-the-shelf FDA approved pharmacological and stimulation modalities to: 1) Determine the optimal stimulation parameters, i.e., electrode placement and stimulation intensity, frequency and duration, for facilitating forelimb fine motor function in rats with a cervical SCI. Using existing FDA-approved epidural electrodes, we will demonstrate in patients with a cervical SCI that cervical EDS can facilitate arm-hand function. 2) Identify an effective mode of administration, define the dose- response pharmacokinetics, and determine the effectiveness of a monoaminergic agonist to facilitate upper limb function after a cervical SCI. We will assess the effectiveness of existing FDA-approved pharmacological agents (i.e., buspirone and as an alternative, bromocriptine), and determine their effectiveness in improving forelimb control in subjects with a cervical SCI. 3) Define the dose-response properties of monoaminergic agonists when combined with EDS in facilitating forelimb function in rats after a cervical SCI. We will demonstrate the efficacy of ES in combination with a pharmacological intervention in facilitating arm and hand function in humans after a cervical SCI. 4) Determine whether motor training of spinal rats will further enhance the recovery of motor function when combined with pharmacological and/or EDS interventions. 5) Develop a protocol for machine learning to enable rapid selection of the optimal pharmacological and EDS parameters for motor recovery in rats and in human subjects. If successful, this could represent the beginning of a paradigm shift in the use of minimally invasive strategies combined with rehabilitative approaches to realize significant improvement in upper limb function after paralysis.